Development of Tricyclic 4,5-Dihydro-3H-pyrrolo[2,3-c]quinolin-4-ones as Potent Autotaxin Inhibitors for Pulmonary Fibrosis Treatment In Vivo.

Autotaxin (ATX) has been recognized as an attractive target due to its hyperactivity in hydrolyzing lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) throughout the initiation and progression of fibrotic diseases. Herein, a hydrophilic amide linker and sp3-rich bicyclic 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one scaffold were employed to modify the lead compound PAT-409, followed by benzene ring fusion to generate novel tricyclic 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one ATX inhibitors. Among them, the pyridine-2-carboxylic derivatives 45 and 46 demonstrated subnanomolar ATX inhibition (IC50 < 1 nM), with a favorable heart safety profile (hERG > 30 μM) and minimal fibroblast toxicity. Significantly, in bleomycin-induced pulmonary fibrosis mouse models, both compounds markedly improved respiratory function and reduced fibrotic lesions. Mechanistic studies revealed that 45 suppressed the TGF-β/Smad signaling pathway, downregulating α-smooth muscle actin (α-SMA) and extracellular matrix components (ECM). Overall, the identification of 45 and 46 for pulmonary fibrosis therapy provides a featured tricyclic scaffold for further development of novel ATX inhibitors.